The biochemical, molecular and cellular events which contribute to narcotic addiction will be investigated. The overall objective of the research is to understand more fully the basic actions of morphine and related narcotic analgesics which are responsible for acute effects and which participate in narcotic tolerance and physical dependence. The research plan contains three novel features. The relatively well defined central thermoregulatory system will be used as the primary physiological index of central narcotic action. Temperature responses offer significant advantages over antinociceptive effects as parameters of narcotic action. Rapid induction of narcotic tolerance will be induced by use of intracerebroventricular and intravenous infusions and by intracerebral microinfusion techniques. Time courses and dose-dependency relationships of narcotic responses will be established and the biochemical parameters will be studied during the acute phase of narcotic action, during tolerance and during withdrawal. Finally, we will collaborate on a simultaneous four-front biochemical attack. The participation and relationships of brain neurotransmitters, cyclic nucleotides, RNA synthesis and protein synthesis, and "narcotic receptors" will be examined in relation to the time- and dose-dependent drug-induced temperature responses. These biochemical processes have all been implicated in narcotic action. We feel that improved understanding of narcotic effects on the relatively "simple" thermoregulatory system will provide considerable insight into their effects on other, more complex, neuronal systems.